L-α-glycerophosphate (αGP), a key constituent in phospholipid metabolism (Kennedy and Weiss, 1956), is abundant in most biological tissues (Dawson, 1958). β-Glycerophosphate (βGP) is a product of enzymatic (Ukita et al., 1955) and alkaline (Clarke and Dawson, 1976) hydrolysis of phospholipids and is formed through the cyclic phosphodiester intermediate 1,2-cyclic glycerophosphate (1,2 cGP) (Ukita et al., 1955; Clarke and Dawson, 1976). 1,2 cGP has been detected in algae species (Boyd et al., 1987) as well as in human cancer tissues (Su et al., 1993). Similarly, αGP can in principle adopt the cyclic form 1,3-cyclic glycerophosphate (1,3 cGP). This compound has been shown to be formed as an intermediate in the phospholipase C hydrolysis of phosphatidyl glycerol (PG) (Shinitzky et al., 1993) and upon further hydrolysis is converted to αGP.
A six-membered cyclic phosphate of foremost biological importance is cyclic AMP. The ring of cyclic AMP is actually a derivative of 1,3 cGP backbone. Other cyclic phosphates which were detected in biological systems include glucose cyclic phosphodiester (Leloir, 1951), 2′,3′-cyclic phosphodiester (Markham and Smith, 1952), riboflavin-4′,5′-cyclic phosphodiester (Forrest and Todd, 1950), myoinositol-1,2-cyclic phosphodiester (Dawson et al., 1971) and cyclic lysophosphatidic acid (Friedman et al., 1996).
Except for cyclic AMP and cyclic GMP which have been extensively studied, no specific biological activities have been so far assigned to the other biological cyclic phosphates.
There are several kinds of disorders and diseases which result from deterioration of areas of the brain and loss of neurons. One example of such diseases are neurodegenerative diseases such as Parkinson's disease (PD). Such diseases often involve degeneration of dopamine-producing neurons. Current therapeutic methods are mostly aimed at continuous stimulation of dopamine receptors by drugs which, although initially providing symptomatic relief, gradually lose effectiveness. Furthermore, such drugs do not prevent the progressive degeneration of dopaminergic neurons characteristics of such diseases.
A large number of growth factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor, brain derived growth factor and glial derived neurotrophic factor (Knusel B., et al., 1990; Knusel et al., 1991; Linn et al., 1993) stimulate dopaminergic neuron survival and differentiation in vitro. In animal models involving induction of Parkinson's disease, the induced animals show improved behavior and an increase in tyrosine hydroxylase (TH), the key enzyme in the dopamine production pathway immunoreactviity when treated with factors like GDNF (Tomac, A. et al. 1995) and ciliary neurotrophic factor (CNTF) (Hagg, T. and Varon 1993).
List of Compounds and Their Abbreviations
The following compounds which formulas are presented in Appendix A just before the claims, will be represented herein in the specification by their abbreviations as follows:    1. 1,3 cyclic glycerophosphate—1,3 cGP    2. 1,2 cyclic glycerophosphate—1,2 cGP    3. 3-acyl 1,2 cyclic glycerophosphate (cyclic lysophosphatidic acid)—c-lysoPA    4. Phenyl 1,3 cGP—P-1,3 cGP    5. Phenyl 1,2 cGP—P-1,2 cGP    6. 1,3 cyclic propanediol phosphate—1,3 cPP    7. 1,2 cyclic propanediol phosphate—1,2 cPP    8. Phenyl 1,3 cPP—P—1,3 cPP    9. Phenyl 1,2, cyclic propanediol phosphate —P-1,2, cPP    10. Cyclic dihydroxyacetone phosphate—cDHAP    11. Phenyl cyclic dihydroxyacetone phosphate —P-cDHAPGlossary
The following is an explanation of some terms used above and in the following description and claims:    CG—the cyclic glycerophosphates and analogs thereof used in the present invention.    Promoting neural cell differentiation—this term relates to the capability of the CGs used in the invention to cause cells to mature into neural cells after contact therewith. Such activity may be assessed by one of many in vitro and in vivo assays such as those described in the examples below. An example for an in vitro assay would be to grow cells capable of differentiating into nerve cells (e.g. PC12 cells) in the presence of a tested compound and to determine nerve outgrowth in the cells by microscopic evaluation. In vivo assays may, for example, involve treatment of animals with injured dopaminergic neurons with the tested compounds and testing of motional and limb tremor parameters as well as in situ determination of molecules associated with dopaminergic transmission in the treated animals.    Target cells—any cells which have the potential to mature into neural cells. Non-limiting examples of such cells are PC 12 and primary brain cells.    Analog—relates to any compound which is derived from one of the cyclic glycerophosphates of the invention and which substantially maintains the activity of the cyclic phosphate from which it was derived, including, for example, deoxy analogs and phenyl esters of the cyclic glycerophosphates, preferably, deoxy analogs.    Substantially maintaining—this term relates to the capability of analogs to promote the activity carried out by the cyclic glycerophosphate from which they were derived to a certain extent. The analog's activity will be considered to be substantially maintained wherein the activity is 30% or above, preferably 50% or above, more preferably 70% or above, and most preferably 90% or above the level of the activity of the cyclic glycerophosphate.    Effective amount—wherein the method of the invention is intended for prevention of a non-desired condition, the term “effective amount” should then be understood as meaning an amount of the active compound which, when administered, results in the prevention of the appearance of the said condition. Prevention of such a condition, e.g. a neurodegenerative condition, may be required prior to the appearance of any symptoms of a disease, e.g. in individuals having a high disposition of developing the disease, or when the compositions are used for the treatment of nerve rescue which is expected after nerve injury. Wherein the compositions or methods are intended for treatment of an ongoing non-desired condition, the term “effective amount” should then be understood as meaning an amount of the active compound which is effective in ameliorating or preventing the enhancement of the treated condition and related symptoms.    Neural promoting activity—this term encompasses a variety of neural related activities which may be promoted in target cells upon their contact with the CGs used in the invention. Such activities include but are not limited to promotion of nerve growth, provision of dopaminotrophic supporting environment in a diseased brain, prevention of nerve degeneration, and nerve rescue.    Prevention or treatment—the term prevention of disorders and diseases is to be understood in accordance with the invention as a reduction in the probability of the appearance of such disorders and diseases in an individual having a high predisposition of developing such disorders and diseases, reducing the extent of the symptoms associated with such disorders and diseases when they occur or completely preventing their appearance.
Treatment of such disorders or diseases in accordance with the invention means ameliorating the symptoms associated with the disorders or diseases, reducing the extent of such symptoms or completely eliminating them.